Alternative Therapies for Major Depressive Disorder: a critical review of the evidence

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Alternative therapies for major depressive
disorder a critical review of the
evidencePresented toIntegrative Mental Health
Care of Oregon20 February, 2009

• James Lake, MD
• Clinical Assistant Professor
• Stanford University, Department of Psychiatry and
  Behavioral SciencesChair, APA Caucus on CAM

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CAM Rx in Psychiatry

• Evidence for select CAM Rx for MDD
• Folate
• St. Johns wort
• Omega-3 fatty acids
• SAMe
• Light therapy
• Acupuncture
• Exercise
• Case vignette

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The emerging context of CAM Rx for depressed mood

• Limited efficacy of conventional Rx in severe
  MDD no benefit in moderate MDD (Kirsch 2008)
  but benefits in sub-group (Thase 2008).
• CAM use greater among individuals diagnosed with
  any DSM-IV disorder (Unutzer 2000).
• Two thirds of severely depressed outpatients use
  CAM Rx while taking prescription medications
  (Kessler 2001).

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CAM Rx trends in mental health

• Two thirds of psych. hospitalized patients used a
  CAM therapy within the past year (Elkins et al.,
  2005).
• Few patients disclose CAM use to family physician
  or psychiatrist resulting in treatment failures,
  delays and safety issues (Eisenberg et al., 1998
  Kessler et al., 2001)

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Evidence for select CAM Rx for MDD

• Folate
• St. Johns wort
• Omega-3 fatty acids
• SAMe
• Light therapy
• Acupuncture
• exercise

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What the research evidence shows

• Select CAM Rx used to treat major depressive
  disorder

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Folate in MDD

• Essential co-factor for synthesis of
  S-adenosyl-methionine (from homocysteine).
• Findings suggest efficacy however optimal dose
  and form of folate unclear.
• RPCT MDD patients randomized to fluoxetine
  folate (0.5mg) improved more than fluox.
  placebo (Coppen Bailey 2000)
• Women only had greater response possibly due to
  folate dose not sufficient to reduce homocysteine
  levels in male patients. Suggests need for higher
  dose or different form as adjunctive Rx in
  depressed males

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Folate in MDD

• Open and blinded studies of methylfolate in
  depressed populations (elderly, concurrent
  alcohol dependence, concurrent dementia) show
  significant improvement in depressive symptoms
  (Guaraldi et al., 1993 Di Palma et al., 1994
  Glória et al., 1997 Passeri et al., 1993)
• RPCT on methylfolate as adjunctive Rx in folate
  deficient adult MDD patients (N 24) showed
  improvement over placebo augmentation (Godfrey et
  al., 1990)

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Folate

• Studies on leucovorin (folinic acid that is
  converted into methylfolate) augmentation in
  non-folate deficient MDD patients who were
  partial responders to SSRIs found significant
  reduction in sx severity and 19 remission
  (Alpert et al., 2002)
• Folate augmentation may enhance response to
  lithium in folate deficient bipolar and unipolar
  depression (Coppen and Chaudhry, 1986)
• Higher end-of-trial folate levels tracked
  clinical improvement in mood

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Folatetreatment issues

• Folate and methylfolate monotherapy may benefit
  certain depressive populations. More studies
  needed to confirm effect size, optimal form and
  dosing
• Folate augmentation is a reasonable choice when
  treating MDD in folate deficient patients,
  including non-responders and partial responders
  to antidepressants
• Depressed individuals with normal folate levels
  may benefit from folate or methylfolate (NOTE
  peripheral folate level may not accurately
  reflect CNS level).

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St. Johns wort(Hypericum perforatum)

• in major depressive disorder

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St. Johns Wort (Hypericum perforatum)

• Cochrane meta-analysis of RCTs on SJW in MDD
  found serious design problems and inconsistent
  outcomes (Linde et al., 2005)
• Two large well designed RPCTs found no difference
  between SJW and placebo on primary outcome
  measures in MDD (Shelton et al., 2001 Hypericum
  Study Group, 2002)
• Another large trial found significant difference
  between St. Johns Wort and placebo in
  mild-moderate depression (Lecrubier et al.,
  2002).

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St. Johns worttreatment issues

• Safety issuesinduces P450 3A4 system reducing
  serum levels of antiretrovirals,
  immunosuppressants, antineoplastic agents,
  anticoagulants, digoxin, OCPs and HRT(Roby et
  al., 2000 Mannel et al., 2004)
• May be reasonable Rx for mild to moderate MDD,
  however recent U.S. studies do not show efficacy
  over placebo and drug interactions limit use and
  pose safety considerations.

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Essential fatty acids

• In major depressive disorder

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Omega-6 Fatty Acids
Omega-3 Fatty Acids
Linoleic Acid (182n-6)
a-Linolenic Acid (183n-3)
?-6 Desaturase
(GLA)? -Linolenic Acid (183n-6)
Stearidonic Acid (184n-3)
Elongase
(DHGLA) Dihomo-?-Linolenic Acid (203n-6)
Eicosatetraenoic Acid (204n-3)
?-5 Desaturase
Eicosanoids
(AA)Arachidonic Acid (204n-6)
(EPA) Eicosapentaenoic Acid (205n-3)
Elongase
245n-3
Eicosanoids Leukotriene 5-series Prostaglandins
E3 Thromboxanes A3
?-6 Desaturase
Eicosanoids Leukotriene 4-series Prostaglandins
E2 Thromboxanes A2
246n-3
ß-Oxidation
(DHA) Docosahexaenoic Acid (226n-3)
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Omega-3s (EPA and DHA)general health benefits

• Found in fish, algae and flaxseed oil
• Deficient in average American
• Cardiovascular benefitsdecrease risk of
  thrombosis and arrhythmias, reduce serum
  triglycerides, decrease atherosclerosis and
  reduce inflammation (Kris-Etherton et al., 2003)
• AHA recommends eating fish at least twice weekly,
  and 1 g/day EPA DHA in individuals with heart
  disease (Kris-Etherton et al., 2003)
• May reduce oxidative damage and slow age-related
  cognitive decline (Cole et al., 2005 Morris et
  al., 2005).

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Omega-3 fatty acids in MDD

• Meta-analyses show benefits in PCRTs of both
  unipolar and bipolar depression (Parker et al.,
  2006 Freeman et al., 2006 Lin and Su, 2007)
• Howeverresults difficult to interpret due to
• Inconsistent findings
• Heterogeneity of study designs
• Stand-alone vs. adjunctive
• EPA vs DHA vs both Omega-3s
• Variability in dosing
• Variability in study length

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Omega-3 fatty acids in MDD

• DHA as monotherapy in adult MDD no benefit over
  placebo (Marangell et al., 2003)
• DHA/EPA monotherapy in childhood MDD moderate
  benefit over placebo (Nemets et al., 2006)
• DHA/EPA adjunctive to antidepressants no benefit
  over placebo (DHA dose higher than EPA) (Grenyer
  et al., 2007)
• EPA (1 g) vs. fluoxetine (20 mg) vs. EPA
  fluoxetine (N60) similar efficacy with EPA and
  fluoxetine. Combined Rx group superior to either
  (Jazayeri et al., 2008)

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Omega-3s in post-partum depression

• Small PRCTs in pregnant and postpartum women with
  mixed findings
• Superiority of omega-3s (EPA and DHA, 3.4 g per
  day) over placebo in pregnant women with MDD, (Su
  et al., 2008)
• No benefit of Omega-3s over placebo in pregnant
  and postpartum women with MDD (Freeman et al.,
  2008 Rees et al., 2008)

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Omega-3streatment issues

• Few mild AEs gastrointestinal discomfort
  (Freeman and Sinha, 2007).
• Theoretical risk of increased bleeding but no
  actual cases of bleeding reported, even in
  cardiovascular studies of high-dose
  supplementation or concomitant anticoagulants
  (Eritsland et al., 1995 Mueller et al., 1991)
• Combined mood and heart benefits make omega-3s
  reasonable Rx option for subset of patients with
  MDD at greater risk for cardiovascular disease.
  (Fraguas et al., 2007)

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Omega-3s in MDDbottom line

• Low-risk augmentation strategy for MDD with
  significant cardiovascular and health benefits
  endorsed by APA subcommittee (Freeman et al.,
  2006)
• Doses of 1-9 grams studied in MDD, most findings
  support lower doses
• Adjunctive EPA or EPA DHA probably most
  beneficial, less evidence for DHA alone.
• Most studies of omega-3s monotherapy in MDD show
  benefit with EPA alone or EPA dose greater than
  DHA.

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S-adenosyl-methionine (SAMe)

• In major depressive disorder

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S-adenosyl-methionine (SAMe)

• Required cofactor for methyl group transfers.
• Early studies used I.M. SAMemarked improvement
  in depressed mood (Agnoli et al.,1975)
• Open studies on IV SAMeimprovement in MDD
  (Mantero et al, 1976 Andreoli et al, 1977
  Salvadorini et al, 1980 Carney et al, 1983
  Labriola et al, 1986 Antun, 1987)
• Single-blind inpatient study on IV SAMerapid
  response with full remission in 7/9 patients, no
  significant AEs (Lipinski et al 1984)

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SAMe

• PCRTsequal efficacy of IV or oral SAMe and
  antidepressants with good tolerance (Mantero et
  al, 1975 Kufferle and Grunberger, 1982 Bell et
  al, 1988 Janicak et al, 1988 De Vanna and
  Rigamonti, 1992 Bell et al, 1994 Delle Chiaie
  et al, 2002 Pancheri et al, 2002).
• Meta-analysis of PCRTs (N1,015)no significant
  differences in outcomes between SAMe and
  antidepressants (AHRQ Publication 2002
  http//www.ahrq.gov)

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SAMetreatment issues

• Stability is an issueSAMe degrades rapidly over
  several months on shelf. (Spillmann and Fava,
  1996).
• Adverse effects mild insomnia, lack of appetite,
  constipation, nausea, dry mouth, sweating,
  dizziness, and nervousness (Spillmann and Fava,
  1996
• Small percentage of responders switch to mania
  (Carney et al., 1987)
• Two large NCCAM-sponsored PCRTs ongoing
• Augmentation of SSRIs with oral SAMe in
  Rx-resistant MDD
• Oral SAMe vs conventional antidepressant

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Light exposure therapy

• In major depressive disorder

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Bright light exposure therapy

• Cochrane systematic reviewall published studies
  on bright light exposure for non-seasonal
  depression found modest though promising
  anti-depressive efficacy, especially when
  administered during the first week of treatment,
  in the morning, and as an adjunctive treatment to
  sleep deprivation responders (Tuuainen et al.,
  2004).

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Bright light exposure therapy

• 2 more recent reviews report mixed findings
• Comparable efficacy of bright light and
  antidepressants for SAD and non-seasonal MDD but
  inconsistent evidence for adjunctive bright light
  therapy for non-seasonal depression (Golden et
  al., 2005)
• Bright light is effective adjuvant to
  antidepressants but ineffective alone in
  non-seasonal depression (Even 2008)

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Light exposure therapydim light

• Early morning exposure to dim red or blue light
  may be as efficacious as bright light, especially
  in SAD (Wileman 2001)
• Exposure to low-intensity artificial light 2
  hours before daylight (dawn simulation) may
  accelerate response to conventional
  antidepressants (Benedetti 2003). More studies
  needed

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Light exposure therapytreatment issues

• Mechanism still unclearexposure to full-spectrum
  bright light probably modulates central levels of
  melatonin and the monamine neurotransmitters
  (Neumeister 2004).
• Safe and effective alternative to antidepressants
  in pregnant depressed women (Epperson 2004)
• Uncommon AEs mild jitteriness, headaches (10),
  mild nausea (16) (Terman 2005)
• Sporadic cases of hypomania reported (Epperson et
  al., 2004 Terman 2005)

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Acupuncture

• In major depressive disorder

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Acupuncture

• Efficacy difficult to evaluate due to
• Heterogeneity in study designs
• Concurrent use of other conventional or CAM Rx
• Differences in Chinese and Western medical
  diagnoses
• Use of different acupuncture treatment protocols
• Three of 4 systematic reviews of acupuncture in
  MDD included only English language studies
  (Mukaino et al, 2005 Smith and Hay, 2005 Leo
  and Ligot, 2007).

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Acupunctureresearch and Rx issues

• Overall no significant clinical differences
  between manual acupuncture and electro-acupuncture
  and sham or waitlist.
• Insufficient data to suggest comparable efficacy
  of acupuncture and antidepressant medications.
• Uncommon AEs bruising, fatigue, and nausea. Rare
  serious complicationsk infection with HIV,
  hepatitis B and C due to use of non-sterilized
  needles (Vincent 2001).

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Acupuncture

• Most recent systematic reviewShanghai University
  School of Medicine (Wang et al 2008).
• Only review to include Chinese-language
  publications. 200 trials identified including 8
  sham controlled studies (total N 477) comparing
  manual acupuncture, electro-acupuncture or laser
  acupuncture, with sham acupuncture only.
• Found general beneficial effects (CGI) in
  depressed patients, however disparate study
  designs and small study sizes preclude
  conclusions about response rates and remission
  rates.

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Acupunctureresearch and Rx issues

• No agreement on standardized sham acupuncture
  protocol and possible beneficial effects from
  stimulating specific acupoints used as sham
  points
• Significant differences in type of acupuncture,
  duration, frequency and number of sessions as
  confounding variables limit analysis of pooled
  treatment outcomes from heterogeneous study
  designs.

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Acupunctureresearch and Rx issues

• Only one of nine studies included in one review
  (Halbreich 2008) examined efficacy of single
  acupoints specific to depression using a
  double-blind sham-controlled paradigm (Allen et
  al 1998).
• A subsequent larger study failed to confirm
  preliminary findings (Allen et al 2006).

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Exercise

• In major depressive disorder

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Exercise

• Epidemiological findings suggest regular exercise
  associated with decreased prevalence of
  depressive symptoms esp in older adults (Brown et
  al., 2005Strawbridge et al., 2002)
• Efficacy difficult to determine in treatment
  studies due to difficulty with blinding the
  treatment assignment to exercise vs. control
  groups, constructing appropriate control
  conditions for comparison groups, and adequate
  follow-up (Lawlor et al., 2001).

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Exercise

• Treatment studies demonstrate benefit of aerobic
  exercise (Dunn et al., 2002 Dunn et al., 2005
  Penninx et al., 2002 Mather et al., 2002
  Blumenthal et al., 1999 Herman et al., 2002)
• Some studies show mood benefits of resistance
  training (Singh et al., 2005 Singh et al.,
  2001)
• Effects of exercise on mood may be sustained over
  time (Babyak et al., 2000). long-term
  longitudinal studies needed

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Challenges

• Definitions and Dx criteria changestudies
  difficult to compare
• High comorbidity rates in MDD population excluded
  from MDD treatment studies limiting
  generalizability of findings
• High placebo response rate in MDD makes
  uncontrolled trials difficult to interpret
• Some CAM Rx difficult to evaluate using RCT
  designs (individualized therapy not reducible to
  Western concepts sham)

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Recommendations

• Many CAM Rx are low risk interventions which may
  benefit and will not harm
• Consensus on CAM research priorities for
  psychiatry (APA task force)
• Better CAM research methodology for improved
  quality (larger size, randomized treatment
  allocation, defining placebo or sham (NCCAM)
• Education and training emphasizing best evidence,
  safety, liability issues (APA task force)

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Bottom line

• Mental health professionals need to know which
  CAM and integrative Rx are safe and effectiveand
  which are unsafe or ineffectivein order to
• Give patients judicious advice
• Refer to appropriate CAM practitioners
• Limit our liability

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Case vignette

• Integrative management of depression

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Case vignette

• 57 year old retired stock broker
• Recovering alcoholic with 11 yrs sobriety
• Elevated cholesterol on statin
• First MDE age 18 fatigue, hopelessness,
  hypersomnolence, frequent SI (resolved without Rx
  after 3 months)
• Subsequent MDEs approx. every 3 to 5 years
  vegetative sx, frequent SI

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Treatment Hx

• First treated age 30 Prozac 20mg with significant
  improvement but discontinued p. 1 yr due to
  sexual AEs and weight gain
• Recurring MDE 3 yrs later Zoloft 150mg, worsened,
  SI, hospitalized LiCO3 augmentation with
  significant improvement
• Discontinued Lithium after 3 months tremor,
  weight gain, nausea.

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Treatment Hx

• Subsequent therapeutic trials on Paxil, Serzone,
  Celexa, Lexapro, Effexor, with initial positive
  results
• Now on Remeron 15mg munchies and weight gain
• They work for a whilethen peter out
• No previous CAM or integrative Rx
• Retired last year and moved to suburbs
• Found integrative clinic and open to new
  approaches

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Integrative RxAssessment and Formulation

• M.D./L.Ac. Does conventional assessment and
  Chinese medical assessment
• Med-psych, social and spiritual hx incl. detailed
  hx of previous conventional and CAM Rx
• Conventional Dx is MDE, recurrent, now with
  moderate depressed mood, consider depressed mood
  due to low cholesterol
• Chinese Dx (pulses, tongue) ascribes mood sx to
  stagnant liver qi
• Labs serum total cholesterol and triglycerides,
  RBC folate level, and thyroid studies

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Integrative treatment planning

• Review of substantiated non-conventional
  approaches for moderate depressed mood auggests
• life style changes
• Acupuncture
• other therapies that improve moderate depressed
  mood when used alone or in combination with
  conventional Rx

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Treatment planningpatient preferences

• Patient skeptical about Chinese medicine which is
  not pursued
• Patient has strong interest in supplements and
  exercise
• Both approaches are beneficial for moderate
  depressed mood
• Both are available options, affordable and
  realistic for patient

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Treatmentinitial integrative recommendations

• Initial plan continue current dose of
  mirtazepine (15mg), start trial on adjunctive
  SAMe with gradual taper to 400mg BID, vitamin
  supplements (B-12, folate), daily aerobic
  exercise, improved diet and regular stress
  management.
• Document informed consent of SAMe trial p.
  reviewing AE risks

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3 week follow-up

• nothing is workinggoing downhill fast
• Still craving sweets, sad all the time,
  demoralized and not exercising
• RBC folate low-normal, serum total cholesterol
  155mg/dl (low NL). Thyroid studies WNL.
• No change in Liver qi stagnation
• Takes B vitamins, SAMe 200mg/am only (inferior
  brand)
• Working in garden, listening to music

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Modified plan

• Change to quality brand of SAMe and continue with
  initial titration schedule to 400mg BID
• Encourage daily work in garden and aerobic
  workouts if motivated
• Encourage listening to music for stress
• Review option of tapering/DC Remeron if
  significant response to SAMe

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2 week follow-up

• Significantly brighter
• Exercising almost daily
• SAMe 400mg BID with mild GI distress
• munchies still a problem
• Family practice MD reduced statin dose, repeat
  total serum cholesterol now 180 (protective
  HDL/LDL ratio)

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One month follow-up

• Mood still improved
• Gradual weight loss
• Sustained exercise program
• Good compliance with SAMe, minimal AEs
• Night-time craving sweets continues
• New Rx recommendation hold Remeron pending
  continued euthymic mood while on maintenance SAMe
  with B-vitamins

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On-going care

• Regular 4-6 week FU X 6 months then quarterly
  pending euthymic on present regimen
• Follow serum cholesterol q 6 months adjust statin
  PRN (DC pending contd weight loss)
• Serial Chinese energetic assessments (pulse dx)
• Maintenance SAMe on-going (MDE recurrent)
• Encourage continued exercise, healthy diet and
  life-style changes
• Consider supportive psychotherapy

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General resources

• Textbook of Integrative Mental Health Care, Lake,
  Thieme Medical Publishers, September, 2006.
• A Clinical Manual of Complementary and
  Alternative Treatments in Mental Health, eds.
  Lake and Spiegel, American Psychiatric Press,
  Inc., January, 2007
• Lake, J. Integrative Mental Health Care A
  Therapists Handbook, Norton, 2009 (in press)

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